Due to disease or trauma, surgeons need to replace bone tissue. They can use bone grafts (autografts or allografts) or synthetic materials to replace bone during surgery. Amongst the types of synthetic materials used to replace bone, surgeons use metals (e.g. stainless steel hip or knee implants), polymers (e.g. polyethylene in acetabular cups), ceramics (e.g. hydroxyapatite as a macroporous bone graft) or inorganic-organic composites (e.g. hydroxyapatite-poly(lactic acid) composites for fixation plates). Many of these synthetic bone replacement materials are not resorbable in the body (within a period appropriate to the healing period) and do not stimulate the formation of new bone around or within the implant.
Materials which have generated particular interest include synthetic calcium phosphate (CaP) bone graft substitutes. Materials of this type can delivered to the intended site of bone regeneration in the form of a delivery system comprising granules incorporated in an organic polymer gel as a carrier, for example a hydrogel (e.g. carboxymethyl cellulose, CMC, based hydrogel).
Such delivery systems are designed to improve the handling of CaP granules, and to ease placement of the bone graft in the surgical site. The carrier is quickly resorbed or dissolved in the body (typically within 3 to 30 days) to expose the CaP granules for graft-bone interaction.
The carrier used in these delivery systems is selected for its handling characteristics, its safety, and its ability to be quickly resorbed or dissolved in the body. Typically, the polymers in the carrier chosen are natural polymers (e.g. collagen or gelatin), or approved synthetic polymers such as carboxymethyl cellulose (CMC). The carrier does not play an active role in bone repair (for example, in the case of carboxymethyl cellulose, hydroxylpropyl methylcellulose or glycerol). The carrier acts as a handling aid, carrying the active CaP granules to the site for bone regeneration and then dissolving or being resorbed.
The carriers referred to herein act as gels. In general terms, the definition of a gel is a jelly-like substance consisting of, by weight, mostly a liquid, but which exists as a solid, exhibiting no flow in the steady state. In a gel, polymer chains (the “solid phase” of the gel) exist in the “liquid phase” of the gel and interact via chemical cross-linking (e.g. covalent bonding) and/or physical interactions (e.g. hydrogen bonding or Van der Waals bonding) between the polymer chains. It is these interactions between the polymer chains that contributes to the structure and viscoelasticity of the gel.
A hydrogel is a specific type of gel in which water makes up the liquid phase. Typically the solid phase (i.e. the polymer) is dispersed in water under the conditions appropriate for the specific hydrogel to be formed. For example, acid soluble type I collagen can be dispersed (dissolved) in water under dilute acidic conditions (e.g. acetic acid) and will form a gel upon warming to 37° C. (with or without pre-neutralisation of the solution with a suitable base).
As gel formation (gelation) only occurs under particular conditions, a mixture of the ingredients of the gel may not actually be in the form of a gel. Such a solution which has not undergone gelation is referred to herein as a “gel solution”. A gel solution undergoes gelation to form a gel.
Silicon has been shown to play an important role in bone formation and in bone metabolism. Work has therefore been done attempting to form silicon-containing bone graft materials. The synthesis of a silicon-substituted hydroxyapatite material is described in WO 98/08773 and corresponding U.S. Pat. No. 6,312,468. Although these materials have been shown to accelerate the rate of bone healing in animal studies and in human clinical studies, these silicon substituted materials are still very insoluble.
Some synthetic CaP biomaterials incorporate silicon ions as silicates. Examples include bioactive glasses, apatite-wollastonite glass ceramics, silicon-substituted hydroxyapatite and silicon-substituted tricalcium phosphate. Guth et al., Key Engineering Materials, Bioceramics, 2006, 309-311, pages 117-120 suggest that a low level of silicon is released from silicon substituted hydroxyapatite into tissue culture medium. A maximum of around 0.5 μg/ml silicon was reported. Gough et al., Biomaterials, 2004, 25, pages 2039-2046 report a foamed silicon-containing bioactive glass which was incubated for 24 hours in culture medium. Cells were cultured in the resulting conditioned medium neat, or diluted 1:1 or 1:4 with the culture medium. Silicon release was reported as 230 μg/ml in the neat eluate, 120 μg/ml when diluted 1:1 in culture medium and 47 μg/ml when diluted 1:4 in culture medium. Xynos et al., Biochem. Biophys. Res. Commun., 2000, 276, pages 461-465 report a bioactive glass Bioglass 45S5 containing 45% SiO2 w/w. 1% w/v particulate of this glass, 710-300 μm diameter, was incubated in Dulbecco's modified eagle medium (DMEM) for 24 hours at 37° C. and remaining particulate removed by filtration. The medium was then supplemented with 10% fetal bovine serum, 2 mM 1-glutamine, 50 U/ml penicillin G, 50 μg/ml streptomycin B and 0.3 μg/ml amphotericin B at 37° C., in 95% air humidity and 5% CO2. The elementary content of calcium, silicon, phosphorus and sodium in this solution was determined by inductively coupled plasma analysis. Xynos et al report a content of 0.19 ppm+/−0.01 Si in the control DMEM, and 16.58 ppm+/−1.78 in the Bioglass 45S5-conditioned DMEM.
PCT/GB2009/002954 (not yet published) describes a more soluble silicate-substituted calcium phosphate hydroxyapatite, having a Ca/P ratio in the range 2.05 to 2.55 and a Ca/(P+Si) molar ratio less than 1.66. These silicon-substituted hydroxyapatites exhibit a high level of solubility compared to hydroxyapatite ceramics or previously reported silicon-substituted hydroxyapatite ceramics, and release high levels of silicon on soaking in solution. For example, approximately 10-100 times as much silicon is released from the silicate-substituted hydroxyapatites described in PCT/GB2009/002954 compared to previously reported silicon-substituted hydroxyapatites.